Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

ABSTRACT

The field of the invention relates to stable dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues, and processes for their preparation. The water content of the dosage form is not more than 6.5% w/w.

FIELD OF THE INVENTION

The field of the invention relates to stable dosage forms comprisingspiro or dispiro 1,2,4-trioxolane antimalarials, or theirpharmaceutically acceptable salts, prodrugs and analogues, and processesfor their preparation.

BACKGROUND OF THE INVENTION

Malaria, the most common parasitic disease of humans, remains a majorhealth and economic burden in most tropical countries. Large areas ofCentral and South America, Hispaniola (Haiti and the DominicanRepublic), Africa, the Middle East, the Indian subcontinent, SoutheastAsia, and Oceania are considered as malaria-risk areas. It leads to aheavy toll of illness and death especially amongst children and pregnantwomen. According to the World Health Organization, it is estimated thatthe disease infects about 400 million people each year, and around twoto three million people die from malaria every year. There are fourkinds of malaria parasites that infect human: Plasmodium falciparum,Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Malaria spreads from one person to another by the bite of mosquito,Anopheles gambiaewhich serves as vector. When a mosquito sucks the bloodof human, sporozoites are transfused into the human body together withsaliva of the mosquito. The sporozoites enter into the hepatocytes,reproduce asexually and finally enter into the blood stream. Theparasites continue to multiply inside the red blood cells, until theyburst and release large number of merozoites. This process continues,destroying a significant number of blood cells and causing thecharacteristic paroxysm (“chills and fever”) associated with thedisease. In the red blood cells, some of the merozoites become male orfemale gametocytes. These gametocytes are ingested by the mosquito whenit feeds on blood. The gametocytes fuse in the vector's gut; sporozoitesare produced and are migrated to the vector's salivary glands.

The clinical symptoms of malaria are generally associated with thebursting of red blood cells causing an intense fever associated withchills that can leave the infected individual exhausted and bedridden.More severe symptoms associated with repeat infections and/or infectionby Plasmodium falciparum include anaemia, severe headaches, convulsions,delirium and, in some instances, death.

Quinine, an antimalarial compound that is extracted from the bark ofcinchona tree, is one of the oldest and most effective drugs inexistence. Chloroquine and mefloquine are the synthetic analogs ofquinine developed in 1940's, which due to their effectiveness, ease ofmanufacture, and general lack of side effects, became the drugs ofchoice. The downside to quinine and its derivatives is that they areshort-acting and have bitter taste. Further, they fail to preventdisease relapses and are also associated with side effects commonlyknown as ‘Chinchonism syndrome’ characterized by nausea, vomiting,dizziness, vertigo and deafness. However, in recent years, with theemergence of drug-resistant strains of parasite andinsecticide-resistant strains of vector, the treatment and/or control ofmalaria is becoming difficult with these conventional drugs.

Malarial treatment further progressed with the discovery of Artemisinin(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactoneisolated from the plant Artemisia annua (Meshnick, S. R. et al.,Microbiol. Rev. 1996, 60, 301-315; Vroman J. A. et al., Curr. Pharm.Design, 1999, 5, 101-138; Dhingra V. K. et al., 2000, 66, 279-300), anda number of its precursors, metabolites and semi synthetic derivativeswhich have shown to possess antimalarial properties. The antimalarialaction of artemisinin is due to its reaction with iron in free hememolecules of the malaria parasite, with the generation of free radicalsleading to cellular destruction. This initiated a substantial effort toelucidate its molecular mechanism of action (Jefford, C., dv. Drug Res.1997, 29, 271-325; Cumming, J. N. et al., Adv. Pharmacol. 1997, 37,254-297) and to identify novel antimalarial peroxides (Dong, Y. andVennerstrom, J. L., Expert Opin. Ther. Patents 2001, 11, 1753-1760).

Although the clinically useful semi synthetic artemisinin derivativesare rapid acting and potent antimalarial drugs, they have severaldisadvantages including recrudescence, neurotoxicity, (Wesche, D. L. etal., Antimicrob. Agents. Chemother. 1994, 38, 1813-1819) and metabolicinstability (White, N. J., Trans. R. Soc. Trop. Med. Hyg., 1994, 88,41-43). A fair number of these compounds are quite active in vitro, butmost suffer from low oral activity (White, N. J., Trans. R. Soc. Trop.Med. Hyg., 1994, 88, 41-43 and van Agtmael et al., Trends Pharmacol.Sci., 1999, 20, 199-205).

Thus there exists a need in the art to identify new peroxideantimalarial agents, especially those which are easily synthesized, aredevoid of neurotoxicity, and which possess improved solubility,stability and pharmacokinetic properties. Following that, many syntheticantimalarial 1,2,4-trioxanes (Jefford, C., Adv. Drug Res. 1997, 29,271-325; Cumming, J. N. et al., Adv. Pharmacol. 1997, 37, 254-297),1,2,4,5-tetraoxanes (Vennerstrom, J. L. et al., J. Med. Chem., 2000, 43,2753-2758), and other endoperoxides have been prepared. Variouspatents/applications disclose means and method for treating malariausing Spiro or dispiro 1,2,4-trioxolanes for example, in U.S. PatentApplication No. 2004/0186168; U.S. Pat. Nos. 6,486,199 and 6,825,230.The present invention relates to solid dosage forms of the various spiroor dispiro 1,2,4-trioxolanes antimalarial compounds disclosed in thesepatents/ applications and are incorporated herein by reference.

Active compounds representing various Spiro and dispiro 1,2,4-trioxolanederivatives possess excellent potency, efficacy against Plasmodiumparasites, and a lower degree of neurotoxicity, in addition to theirstructural simplicity and ease of synthesis. Furthermore, thesecompounds have half lives which are believed to permit short-termtreatment regimens comparing favorably to other artemisinin-like drugs.In general, the therapeutic dose of trioxolane derivative may rangebetween about 0.1-1000 mg/kg/day, in particular between about 1-100mg/kg/day. The foregoing dose may be administered as a single dose ormay be divided into multiple doses. For malaria prevention, a typicaldosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning1-2 weeks prior to malaria exposure continued up to 1-2 weekspost-exposure.

However, in spite of many advantages of trioxolanes, there are certainlimitations for formulators developing formulations with trioxolones,the first being their susceptibility to degradation in presence ofmoisture that results in reduced shelf lives. Another is their bittertaste, which can result in poor compliance of the regimen or selectionof another, possibly less effective, therapeutic agent.

We have now discovered that a stable antimalarial oral solid dosage formcomprising Spiro or dispiro 1,2,4-trioxolanes can be prepared bycontrolling the water content below a certain critical limit. Furtherthe bitter taste can be masked by applying a film coating layer to thesolid dosage form.

SUMMARY OF THE INVENTION

In one general aspect there is provided a stable oral solid dosage formthat includes a therapeutically effective amount of a compound havingthe structure of Formula I,

and its enantiomers, diastereomers, polymorphs, pharmaceuticallyacceptable salts and pharmaceutically acceptable solvates, wherein:

R₁ and R₂ are same or different and are selected from hydrogen,substituted or unsubstituted linear or branched alkyl, aryl, and alkarylgroups and substituted or unsubstituted alicyclic groups that areoptionally interrupted by one or more oxygen, sulfur or nitrogen atoms,substituted or unsubstituted aromatic or heterocyclic groups that may beinterrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxygroup, and a halogen, and further providing that the spirocyclohexylring attaching R₁ and R₂ are optionally interrupted by one or moreoxygen, sulfur, or nitrogen atoms; and one or more pharmaceuticallyacceptable excipients, wherein not more than 5% w/w total relatedsubstances are formed on storage at 40±2° C. and 75±5% relative humidityover a period of 6 months.

Embodiments of the oral solid dosage form may include one or more of thefollowing features. For example, the dosage form may include one or moreof other antimalarial drugs. The other antimalarial drugs may includequinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine,dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil,atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289(pafuramidine maleate), clindamycin, their salts and derivativesthereof. In particular, piperaquine, lumefantrine and DB 289 may beused.

The pharmaceutically acceptable excipients may include one or more ofbinders, diluents, glidants/lubricants, disintegrants, surfactants andcoloring agents.

In another aspect there is provided a stable oral solid dosage form of atherapeutically effective amount of a compound having the structure ofFormula I, which is formulated using a dry or non-aqueous process.

The solid dosage form may be in the form of a tablet and the tablet maybe coated.

In another general aspect there is provided a process for thepreparation of a stable oral solid dosage form. The process includesblending a compound having the structure of Formula I and one or moreintragranular excipients; granulating the blend to form granules;blending the granules with one or more extragranular excipients; andcompressing the blend into tablet or filling into capsule.

Embodiments of the process may include one or more of the followingfeatures. For example, the granulation may be wet granulation and thewet granulation may include a non-aqueous granulating liquid selectedfrom ethanol, isopropyl alcohol, acetone, dichloromethane, and a bindersolution. The granulation may be dry granulation and the dry granulationmay be compaction or slugging. In particular, the dry granulation may becompaction for example, dry roller compaction.

The tablet may be coated with one or more film coating layers.

In another general aspect there is provided a process for thepreparation of a stable oral solid dosage form. The process includesblending a compound having the structure of Formula I, and one or morepharmaceutically acceptable excipients; directly compressing the blendinto tablet or filling into capsule; and optionally applying one or morefilm coating layers to the tablet.

In another general aspect there is provided a process for thepreparation of a stable oral solid dosage form. The process includesgranulating a blend of one or more excipients; drying the excipientgranules; blending excipient granules with a compound having thestructure of Formula I, or with granules comprising a compound havingthe structure of Formula I; compressing the blend into tablet or fillinginto capsule; and optionally applying one or more film coating layers tothe tablet.

Embodiments of the process may include one or more of the followingfeatures. For example, the granulation may be wet granulation and thewet granulation may include a granulating liquid selected from water,ethanol, isopropyl alcohol, acetone, dichloromethane, and a bindersolution. The granulation may be dry granulation and the dry granulationmay be compaction or slugging. In particular, the dry granulation may becompaction for example, dry roller compaction.

In another general aspect there is provided a method of prophylaxis ortreatment of malaria. The method includes administering a solid dosageform that includes a therapeutically effective amount of a compoundhaving the structure of Formula I; and one or more pharmaceuticallyacceptable excipients, wherein not more than 5% w/w total relatedsubstances are formed on storage at 40±2° C. and 75±5% relative humidityover a period of 6 months.

Embodiments of the oral solid dosage form may include one or more of thefollowing features. For example, the dosage form may include one or moreother antimalarial drugs. The other antimalarial drugs may includequinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine,dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil,atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289(pafuramidine maleate), clindamycin, their salts and derivativesthereof. In particular, piperaquine, lumefantrine and DB 289 may beused.

In another aspect there is provided a method of prophylaxis or treatmentof malaria. The method includes administering a solid dosage form thatincludes a therapeutically effective amount of a compound having thestructure of Formula I, which is formulated using a dry or non-aqueousprocess.

In another aspect there is provided a stable oral solid dosage form. Thedosage form includes a therapeutically effective amount of a compoundhaving the structure of Formula I; at least one other antimalarial drugselected from lumefantrine, piperaquine, or DB 289; and one or morepharmaceutically acceptable excipients.

Embodiments of the oral dosage form may include one or more of thefollowing features. For example, the water content of the dosage formmay not be more than 6.5% w/w.

In another general aspect there is provided a stable oral solid dosageform. The dosage form includescis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane hydrogen maleate; piperaquine; and oneor more pharmaceutically acceptable excipients.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects and advantages of the invention will beapparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

We have now discovered that stable solid oral dosage forms of Spiro ordispiro 1,2,4-trioxolane antimalarials can be prepared which do notdegrade significantly and provide acceptable shelf life.

The term “stable” as used herein refers to chemical stability of activecompound in solid dosage forms against decomposition occurring duringshelf life due to hydrolysis, wherein not more than 5% w/w total relatedsubstances are formed on storage at 40±2° C. and 75±5% relative humidityover a period of 6 months.

The term “solid dosage form” as used herein includes tablets or coatedtablets, capsules, pellets, pills, granules, powders, and the like. Aparticularly suitable solid dosage form is that of tablets.

The present invention provides stable oral solid dosage forms of activecompound, by using excipients having low water content and manufacturedusing dry or non-aqueous formulation processes.

The term “active compound” as used herein includes spiro or dispiro1,2,4-trioxolane compound of Formula I

wherein R₁ and R₂ are same or different and are selected from hydrogen,substituted or unsubstituted linear or branched alkyl, aryl, and alkarylgroups and substituted or unsubstituted alicyclic groups that areoptionally interrupted by one or more oxygen, sulfur or nitrogen atoms,substituted or unsubstituted aromatic or heterocyclic groups that may beinterrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxygroup, and a halogen, and further providing that the spirocyclohexylring attaching R₁ and R₂ are optionally interrupted by one or moreoxygen, sulfur, or nitrogen atoms. In particular, it includes compoundsof Formula I, wherein R₁ is hydrogen, for example, compounds having thestructure of Formula II.

Active compound includes one or more of the various spiro and dispirotrioxolane derivatives disclosed in U.S. Application No. 2004/0186168;U.S. Pat. Nos. 6,486,199 and 6,825,230 and are incorporated herein byreference. These trioxolanes are relatively sterically hindered on atleast one side of the trioxolane heterocycle which provides better invivo activity, especially with respect to oral administration.Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possessexcellent potency and efficacy against Plasmodium parasites, and a lowerdegree of neurotoxicity.

Active compound includes free form of the compounds referred to hereinas well as their pharmaceutically acceptable salts, solvates, esters,enantiomers, diastereomers, polymorphs, metabolites, prodrugs andanalogues. In particular, active compound iscis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decanehydrogen maleate.

It has been observed through exhaustive experimentation that when activecompound is formulated into dosage forms, including liquid as well assolid dosage forms, it gets degraded by hydrolysis. The degradation maybe due to water associated with the excipients or added during thecourse of processing. Thus, liquid oral dosages forms such as aqueoussyrups, suspensions or solutions having desired shelf life could not besuccessfully prepared. Further, preparation of solid oral dosage formsof active compound, using techniques involving use of water such as wetgranulation, spray drying, or extrusion-spheronization processesresulted in dosage forms with wavering stability results. However,acceptable stability results were obtained when the solid dosage formswere formulated using appropriate excipients with low water content anda process in which water was absent such as dry granulation, directcompression or non-aqueous granulation. In case where excipients weregranulated using water, the excipient granules were dried appropriatelybefore blending with active compound as such or with active compoundcontaining granules, and processed into solid dosage forms of acceptablestability.

The role of excipients and water content was evaluated by conductingcompatibility studies of active compound with various excipients, indifferent proportions and evaluating the extent of degradation by forceddegradation at 60° C. over the period of 2 weeks and at 50° C. for 4weeks. The water content was analyzed using Karl Fischer method and thetotal related substances (% w/w) were determined by HPLC method. Theresults of the study are represented below in Table 1.

TABLE 1 Compatibility studies of active compound with various excipientsTotal Related Substance (% w/w) After 4 After 2 Drug: Water weeks/weeks/ Excipient Excipient (% w/w) Initial 50° C. 60° C. Croscarmellosesodium 1:0.5 0.59 0.09 0.34 0.35 Cross povidone 1:0.5 3.49 0.13 0.400.68 Sodium starch glycolate 1:0.5 1.43 0.13 0.43 0.89 Hydroxypropyl1:0.5 1.22 0.17 0.70 1.05 methylcellulose 5 cps Polyvinyl pyrrolidone K1:0.5 3.02 0.00 0.33 0.79 30 Sodium lauryl sodium 1:0.5 0.79 0.15 0.921.59 Opadry ® 1:0.5 0.46 0.17 1.85 0.96 Titanium dioxide 1:0.5 0.18 0.160.57 0.93 Talc 1:0.1 0.12 0.15 0.63 0.90 Mg. Stearate 1:0.1 0.46 0.130.65 0.86 Aerosol 1:0.1 0.27 0.14 0.66 0.86 Polyethylene glycol 4001:0.1 0.88 0.14 0.66 0.68 Microcrystalline cellulose 1:2 3.69 0.19 0.700.74 Starch 1:2 4.73 0.08 0.60 0.74 Dicalcium phosphate 1:2 2.01 0.070.77 1.32 Pearlitol 1:2 0.02 0.14 0.72 0.77 Micro crystalline cellulose1:10 4.94 0.39 0.78 1.02 Starch 1:10 — 0.07 0.60 4.13 Dicalciumphosphate 1:10 2.14 0.17 0.61 6.07 Pearlitol 1:10 0.52 0.14 0.46 0.70

The study clearly indicates the importance of use of excipients havinglow water or moisture content in stabilizing solid dosage forms ofactive compound. In the present invention, we have discovered that theuse of excipients having water content less than 6.5% w/w surprisinglyincreases the stability of the active compound, and thus providesreasonably long shelf lives. Starch was found to be incompatible withactive compound when used in higher amounts. Further, lactose was alsofound to be incompatible due to degradation by other mechanisms such asMaillard reaction, and dicalcium phosphate was not preferred due toincrease in related substances at 60° C. Microcrystalline cellulose,however, gave the most satisfactory results.

The stable oral solid dosage forms of the present invention may furthercomprise one or more pharmaceutically acceptable excipients, whichinclude all physiologically inert excipients used in the art for thepreparation of solid dosage forms. Examples include binders, diluents,glidants/ lubricants disintegrants, surfactants, coloring agents, andthe like. The excipients may be used either intragranularly orextragranularly, or both. The weight ratio of active compound andexcipients in the dosage forms may vary from about 1.5:1 to about 1:30.

Examples of ‘binders’ include methyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gumarabic, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth,sodium alginate, and the like.

Examples of ‘diluents’ include cellulose powdered, microcrystallinecellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin,lactitol, mannitol, sorbitol, sucrose, sugar compressible, sugarconfectioners, and the like.

Examples of ‘disintegrants’ include clays, celluloses, alginates, gums,cross-linked polymers (such as cross-linked polyvinylpyrrolidone andcross-linked sodium carboxymethylcellulose), sodium starch glycolate,low-substituted hydroxypropyl cellulose, soy polysaccharides, and thelike.

Examples of ‘lubricants’ or ‘glidants’ include talc, magnesium stearate,calcium stearate, stearic acid, colloidal silicon dioxide, magnesiumcarbonate, magnesium oxide, calcium silicate, microcrystallinecellulose, mineral oil, waxes, glyceryl behenate, polyethylene glycol,sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate,sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose estersof fatty acid, microcrystalline wax, yellow beeswax, white beeswax, andthe like.

Examples of ‘surfactants’ include both non-ionic and ionic (cationic,anionic and zwitterionic) surfactants suitable for use in sweetenercompositions. These include polyethoxylated fatty acids and itsderivatives, for example polyethylene glycol 400 distearate,polyethylene glycol—20 dioleate, polyethylene glycol 4-150 monodilaurate, polyethylene glycol—20 glyceryl stearate; alcohol—oiltransesterification products, for example polyethylene glycol—6 cornoil; polyglycerized fatty acids, for example polyglyceryl—6 pentaoleate;propylene glycol fatty acid esters, for example propylene glycolmonocaprylate; mono and diglycerides for example glyceryl ricinoleate;sterol and sterol derivatives; sorbitan fatty acid esters and itsderivatives, for example polyethylene glycol—20 sorbitan monooleate,sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, forexample polyethylene glycol—20 cetyl ether, polyethylene glycol—10-100nonyl phenol; sugar esters, for example sucrose monopalmitate;polyoxyethylene—polyoxypropylene block copolymers known as “poloxamer”;ionic surfactants, for example sodium caproate, sodium glycocholate, soylecithin, sodium stearyl fumarate, propylene glycol alginate, octylsulfosuccinate disodium, and palmitoyl carnitine.

The ‘coloring agents’ include any FDA approved colors for oral use.

The solid dosage forms may further be coated with one or more functionaland/or non-functional layers comprising film-forming polymers, and othercoating additives.

Examples of ‘film-forming polymers’ include cellulose derivatives suchas ethyl cellulose, hydroxypropyl methylcellulose,hydroxypropylcellulose, methylcellulose, carboxymethylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzedpolyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulosephthalate, cellulose acetate phthalate, cellulose acetate trimellitate;waxes such as polyethylene glycol; methacrylic acid polymers such asEudragit® RL and RS; and the like. Alternatively, commercially availablecoating compositions comprising film-forming polymers marketed undervarious trade names, such as Opadry® may also be used for coating.

The ‘coating additives’ include plasticizers, glidants or flowregulators, opacifiers and lubricants.

The pharmaceutical acceptable excipients and/or film forming polymersand coating additives may be selected to provide immediate releaseprofile or modified release profile.

Solid dosage forms of active compound may be prepared by densifyingactive compound and one or more excipients, and processing into soliddosage forms. Densification may be carried out using any conventionalmethod known in the art. In particular, granulation orextrusion-spheronization may be used.

In one of the embodiments, stable oral tablet of active compound may beprepared by a process comprising the steps of blending active compoundand intragranular portion of a diluent, lubricant, and disintegrant;passing the blend through a roller compactor to form a compact mass;reducing the compact into granules of suitable size; blending thegranules with extragranular portion of a lubricant, disintegrant, anddiluent in a double cone blender; and finally compressing into tabletsusing suitable tooling.

In another embodiment, stable oral tablet of active compound may beprepared by a process comprising the steps of blending active compound,intragranular portion of a diluent, lubricant, and disintegrant;compressing the blend in a heavy tabletting press to form slugs;reducing the slugs into granules of suitable size; blending the granuleswith extragranular portion of a lubricant, disintegrant, and diluent ina double cone blender; and finally compressing into tablets usingsuitable tooling.

In another embodiment, stable oral capsule of active compound may beprepared by a process comprising the steps of blending active compound,intragranular portion of a diluent, lubricant, and disintegrant; passingthe blend through a roller compactor to form a compact mass; reducingthe compact into granules of a suitable size; blending the granules withextragranular portion of a lubricant in a double cone blender; andfinally filling into capsules of a suitable size.

In another embodiment, stable oral capsule of active compound may beprepared by a process comprising the steps of blending active compound,intragranular portion of a diluent, lubricant, and disintegrant;compressing the blend in a heavy tabletting press to form slugs;reducing the slugs into granules of a suitable size; blending thegranules with extragranular portion of lubricant in a double coneblender; and finally filling into capsules of a suitable size.

In another embodiment, stable oral tablet of active compound may beprepared by a process comprising the steps of blending active compound,a diluent, a lubricant and a disintegrant; and directly compressing intotablets using suitable tooling.

In another embodiment, stable oral capsule of active compound may beprepared by a process comprising the steps of blending active compound,a diluent, and a lubricant; and filling into capsules of a suitablesize.

In another embodiment, stable oral tablet of active compound may beprepared by a process comprising the steps of blending active compound,intragranular portion of a diluent, and disintegrant; wet granulatingthe blend with a non aqueous granulating fluid or a solution/dispersionof pharmaceutically acceptable excipients in the non-aqueous granulatingfluid; drying and reducing the granules to a suitable size, blending thegranules with extragranular portion of a lubricant, disintegrant anddiluent in a double cone blender; and finally compressing into tabletsusing suitable tooling.

In yet another embodiment, stable oral capsule of active compound may beprepared by a process comprising the steps of blending active compound,intragranular portion of diluent, and disintegrant; wet granulating theblend with a non aqueous granulating fluid or a solution/dispersion ofpharmaceutically acceptable excipients in the non-aqueous granulatingfluid; drying and reducing the granules to a suitable size, blending thegranules with extragranular portion of lubricant, in a double coneblender; and finally filling into capsules of a suitable size.

Examples of ‘non-aqueous granulating fluid’ include organic solventssuch as methanol, ethanol, isopropyl alcohol, dichloromethane, acetone,and the like.

In yet another embodiment, tablets prepared by any of the abovedescribed processes may further be coated with film forming polymers andone or more coating additives, using techniques well known in the artsuch as spray coating in a conventional coating pan or a fluidized bedprocessor; or dip coating. Alternatively, coating can also be performedusing a hot melt technique.

The coating layers over the tablet may be applied as asolution/dispersion of coating components in a suitable solvent.Examples of solvents used for preparing a solution/dispersion of thecoating ingredients include methyl alcohol, ethyl alcohol, isopropylalcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylenechloride, water and the like, and mixtures thereof.

In still another embodiment, one or more of another antimalarial drugselected from piperaquine, lumefantrine, and DB 289 (pafuramidinemaleate) may be added in the blend comprising active compound, in any ofthe embodiments above.

The invention described herein is further illustrated by the followingexamples, which should not be construed as limitation the scope of theinvention.

EXAMPLE 1

Ingredients % w/w Intragranular Maleate salt of a compound of Formula II(active 43.2 compound) Microcrystalline Cellulose 46.67 Magnesiumstearate 0.75 Extragranular Microcrystalline Cellulose 5.63Croscarmellose sodium 3.0 Magnesium stearate 0.75 Coating Opadry ® OY SS58910 white 2.5 Water q.s Total weight 615 Water content <6.55% w/w

Procedure:

1. Active compound and intragranular portion of microcrystallinecellulose were sieved through sieve BSS# 44 and mixed together in adouble cone blender to form a uniform blend.

2. To the blend of step 1, intragranular portion of sifted magnesiumstearate was added and blended for about 5 minutes.

3. The blend of step 2 was compacted in a roller compactor and wassifted through sieve BSS # 22 to form granules.

4. Extragranular portion of microcrystalline cellulose, croscarmellosesodium and magnesium stearate were sieved through sieve BSS # 44 andblended with the granules of step 3.

5. The blend of step 4 was compressed using suitable size punches toobtain compressed tablets.

6. The tablets as obtained from step 5 were coated with Opadry® usingconventional coating techniques.

The tablets prepared as per Example 1 were subjected to stabilitystudies at 25° C./RH 60%, 30° C./RH 65% and 40° C./RH 75% over a periodof 6 months. The results are summarized in Table 2. The results of invitro drug release analyzed at predetermined time periods are given inTable 3.

TABLE 2 Total related substances (% w/w) 1 2 3 6 Storage ConditionInitial months months months months 25° C. and 60% relative 0.11 — —0.27 0.28 humidity 30° C. and 65% relative 0.11 0.37 0.27 0.29 0.34humidity 40° C. and 75% relative 0.11 0.55 0.67 1.40 1.82 humidity * %Total Related Substance should not be more than 5%

TABLE 3 Percentage (%) of In vitro drug release in USP II apparatus(media: 2% tween 80 in water, 900 ml 75, rpm, in 45 min) 1 2 3 6 StorageCondition Initial months months months months 25° C. and 60% relative 93— — 101 95 humidity 30° C. and 65% relative 93 98 93 94 96 humidityTemperature 40° C. and 93 98 96 92 94 75% relative humidity *The invitro drug release (% w/w) should not be less than 70% (Q) of thelabeled amount dissolved in 45 minutes.

As evident from the above studies, the tablets prepared by the processof the present invention in which water is absent shows acceptable shelfstability.

EXAMPLE 2

Ingredients % w/w 1 Maleate salt of a 44.33 compound of Formula II(active compound) 2 Microcrystalline Cellulose 51.17 3 Magnesiumstearate 1.5 4 Croscarmellose sodium 3.0 Total weight 600 mg Watercontent <6.5%

Procedure:

1. Active compound, microcrystalline cellulose, croscarmellose sodiumand magnesium stearate were sifted through sieve BSS# 44.

2. Sifted active compound, microcrystalline cellulose, andcroscarmellose sodium were mixed in a double cone blender for about 15minutes to form a uniform blend.

3. To the blend of step 2, sifted magnesium stearate was added and mixedfor about 5 minutes.

4. The blend obtained in step 3 was directly compressed using suitablesize capsule shape punches to obtain compressed tablets.

EXAMPLES 3 AND 4

Ingredients Example 3 % w/w Example 4 % w/w Intragranular Maleate saltof a compound of 7.68 13.8 Formula II (active compound) Piperquinephosphate 61.80 55.5 Microcrystalline Cellulose 20.39 21.05 Magnesiumstearate 0.44 0.39 Crospovidone 2.21 1.99 Extragranular MicrocrystallineCellulose 4.42 3.99 Crospovidone 2.21 1.99 Magnesium stearate 1.05 1.09Coating Opadry ® O2B53782 orange 2.5 2.5 Water q.s q.s Total weight (mg)1332.5 738 Water content <6.55% w/w <6.55% w/w

Procedure:

1. Active compound, piperaquine phosphate and intragranular portion ofmicrocrystalline cellulose and crospovidone were sieved through sieveBSS # 44 and mixed together in a double cone blender to form a uniformblend.

2. To the blend of step 1, intragranular portion of sifted magnesiumstearate was added and blended for about 5 minutes.

3. The blend of step 2 was compacted in a roller compactor and wassifted through sieve BSS # 18 to form granules.

4. Extragranular portion of microcrystalline cellulose and crospovidonewere sieved through sieve BSS # 44 and blended with the granules of step3.

5. Extragranular portion of magnesium stearate were sieved through sieveBSS # 44 and blended with the blend of step 4, in a double cone blenderfor about 5 minutes.

6. The blend of step 5 was compressed using suitable size punches toobtain compressed tablets.

7. The tablets as obtained from step 6 were coated with Opadry® usingconventional coating techniques and weight built of up to 2.5% w/w.

The tablets prepared as per the Example 3 & 4 were subjected tostability studies at 40° C./RH 75% over a period of 3 months, asrepresented in Table 4.

TABLE 4 % total related substances (% w/w) 1 2 3 Ingredient Initialmonth months months Maleate salt of a Example 3 0.19 0.27 0.44 0.54compound of Formula II Example 4 0.25 0.32 0.45 0.54 Piperaquinephosphate Example 3 1.16 1.1 1.11 1.16 Example 4 1.15 1.03 1.13 1.16 * %Total related substance should not be more than 5%

While several particular formulations have been described, it will beapparent that various modifications and combinations of the formulationsdetailed in the text can be made without departing from the spirit andscope of the invention. For example although the tablet dosage form hasbeen prepared, other conventional solid dosage forms like capsule canalso be prepared using the similar compositions. Accordingly, it is notintended that the inventions be limited, except as by the appendedclaims.

1. A stable oral solid dosage form comprising: (a) a therapeuticallyeffective amount of a compound having the structure of Formula I,

and its enantiomers, diastereomers, polymorphs, pharmaceuticallyacceptable salts and pharmaceutically acceptable solvates, wherein: R₁and R₂ are same or different and are selected from hydrogen, substitutedor unsubstituted linear or branched alkyl, aryl, and alkaryl groups andsubstituted or unsubstituted alicyclic groups that are optionallyinterrupted by one or more oxygen, sulfur or nitrogen atoms, substitutedor unsubstituted aromatic or heterocyclic groups that may be interruptedby one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and ahalogen, and further providing that the spirocyclohexyl ring attachingR₁ and R₂ are optionally interrupted by one or more oxygen, sulfur, ornitrogen atoms; and (b) one or more pharmaceutically acceptableexcipients, wherein not more than 5% w/w total related substances areformed on storage at 40±2° C. and 75±5% relative humidity over a periodof 6 months.
 2. The stable solid dosage form according to claim 1,wherein the compound has the structure of Formula II.


3. The stable solid dosage form according to claim 1, wherein the dosageform further comprises one or more of other antimalarial drugs selectedfrom quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine,dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil,atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline,clindamycin, and DB
 289. 4. A stable oral solid dosage form comprising:(a) a therapeutically effective amount of a compound having thestructure of Formula II,

and its enantiomers, diastereomers, polymorphs, pharmaceuticallyacceptable salts and pharmaceutically acceptable solvates; (b)piperaquine; and (c) one or more pharmaceutically acceptable excipients.5. The stable solid dosage form according to claim 4, wherein not morethan 5% w/w total related substances are formed on storage at 40±2° C.and 75±5% relative humidity over a period of 3 months.
 6. The stablesolid dosage form according to claim 1 or 4, wherein thepharmaceutically acceptable excipients comprises one or more of binders,diluents, glidants/lubricants, disintegrants, surfactants and coloringagents.
 7. The stable solid dosage form according to claim 7, whereinthe diluent is microcrystalline cellulose.
 8. The stable solid dosageform according to claim 7, wherein water content of the excipients isnot more than 6.5% w/w.
 9. The stable solid dosage form according toclaim 1 or 4, wherein the dosage form comprises a tablet, capsule, pill,granule and powder.
 10. The stable solid dosage form according to claim9, wherein the tablet is coated with one or more functional and/ornon-functional coating layers comprising film-forming polymers andcoating additives.
 11. The stable solid dosage form according to claim10, wherein the coating additives comprises one or more of plasticizers,glidants or flow regulators, opacifiers and lubricants.
 12. The stablesolid dosage form according to claim 1 or 4, wherein the dosage formprovides immediate release profile or modified release profile.
 13. Thestable oral solid dosage form according to claim 1 or 4, wherein thedosage form is prepared using a dry or non-aqueous process.
 14. Thestable solid dosage form according to claim 1, wherein the dosage formis prepared by a process comprising the steps of: (a) blending acompound of Formula I and, optionally, one or more other antimalarialdrugs, and one or more intragranular excipients; (b) granulating theblend by roller compaction; (c) blending the granules with one or moreextragranular excipients; and (d) compressing the blend into tablets orfilling into capsules.
 15. The stable solid dosage form according toclaim 1, wherein the dosage form is prepared by a process comprising thesteps of: (a) blending a compound of Formula I and, optionally, one ormore other antimalarial drugs, and one or more intragranular excipients;(b) granulating the blend by slugging; (c) blending the granules withone or more extragranular excipients; and (d) compressing the blend intotablets or filling into capsules.
 16. The stable solid dosage formaccording to claims 1, wherein the dosage form is prepared by a processcomprising the steps of: (a) blending a compound of Formula I and,optionally, one or more other antimalarial drugs, and one or morepharmaceutically acceptable excipients; and (b) directly compressing theblend into tablets or filling into capsules.
 17. The stable solid dosageform according to claim 1, wherein the dosage form is prepared by aprocess comprising the steps of: (a) blending a compound of Formula Iand, optionally, one or more other antimalarial drugs, and one or moreintragranular excipients; (b) wet granulating the blend with anon-aqueous granulating fluid; (c) drying and reducing the granules to asuitable size; (d) blending the granules with one or more extragranularexcipients; and (e) compressing into tablets or filling into capsules.18. The stable solid dosage form according to claim 1, wherein thedosage form is prepared by a process comprising the steps of: (a)granulating a blend of one or more excipients; (b) drying the excipientgranules; (c) blending excipient granules with a compound of Formula Iand, optionally, one or more other antimalarial drugs; and (d)compressing the blend into tablets or filling into capsules.
 19. Amethod of prophylaxis or treatment of malaria, the method comprisingadministering a stable oral solid dosage form comprising: (a) atherapeutically effective amount of a compound having the structure ofFormula I,

and its enantiomers, diastereomers, polymorphs, pharmaceuticallyacceptable salts and pharmaceutically acceptable solvates, wherein: R₁and R₂ are same or different and are selected from hydrogen, substitutedor unsubstituted linear or branched alkyl, aryl, and alkaryl groups andsubstituted or unsubstituted alicyclic groups that are optionallyinterrupted by one or more oxygen, sulfur or nitrogen atoms, substitutedor unsubstituted aromatic or heterocyclic groups that may be interruptedby one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and ahalogen, and further providing that the spirocyclohexyl ring attachingR₁ and R₂ are optionally interrupted by one or more oxygen, sulfur, ornitrogen atoms; and (b) one or more pharmaceutically acceptableexcipients, wherein not more than 5% w/w total related substances areformed on storage at 40±2° C. and 75±5% relative humidity over a periodof 6 months.
 20. The method of prophylaxis or treatment of malariaaccording to claim 19, wherein the dosage form further comprises one ormore of other antimalarial drugs.